CJASN ePress. Published on August 26, 2010 as doi: 10.2215/CJN.04670510 In-Depth Review The Evidence-Based Use of Thiazide Diuretics in Hypertension and Nephrolithiasis Robert F. Reilly,* Aldo J. Peixoto,† and Gary V. Desir† *VA North Texas Heath Care System, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and †VA Connecticut Health Care System, Yale University School of Medicine, New Haven, Connecticut Thiazide-type diuretics are commonly used in the treatment of hypertension and nephrolithiasis. Evidence from randomized clinical trials needs to be considered in decisions about agent choice and dose. In nephrolithiasis, one of the major limitations of the literature is a paucity of data on the dose-response effect of hydrochlorothiazide (HCTZ) on urinary calcium excretion. The best available evidence for prevention of stone recurrence suggests the use of indapamide at 2.5 mg/d, chlorthalidone at 25 to 50 mg daily, or HCTZ 25 mg twice a day or 50 mg daily. In hypertension, chlorthalidone (12.5 to 30 mg daily) may be the best choice when a diuretic is used for initial therapy, with indapamide (1.5 mg daily) being a valuable alternative for older patients. When adding a thiazide to other drug classes, indapamide (2.5 mg daily) has demonstrated value in hypertensive patients who have had a stroke, and HCTZ (12.5 to 25 mg daily) has a safe track record in several patient groups. Although chlorthalidone has not been tested as add-on therapy, the authors believe it is a safe option in such cases. Clin J Am Soc Nephrol 5: ●●●–●●●, 2010. doi: 10.2215/CJN.04670510 rnst stated “the practitioner who bases decisions on diuretics: chlorthalidone (phthalimidine), metolazone (quina- evidence from randomized trials expecting to see sim- zolinone), and indapamide (indoline) (Figure 1). Thiazide-like E ilar benefits in practice should use the doses of antihy- diuretics bind and inhibit the Na-Cl cotransporter in the distal pertensive drugs that were used in trials” (1). Although this convoluted tubule and connecting tubule but do not contain the statement seems intuitively obvious, it is commonly violated in benzothiadiazine core. The term thiazide diuretics will be used the prescribing practices of thiazide diuretics when used for the hereafter to refer to thiazide and thiazide-like diuretics. treatment of hypertension or nephrolithiasis. Not only with respect to the dose used, but also with respect to the individual Thiazide Diuretics and Nephrolithiasis thiazide diuretic used. For example, despite the more compel- In 1959, Lamberg and Kuhlba¨ck found that chlorothiazide (1 ling data in hypertension involving chlorthalidone use (1,2), g twice daily) and HCTZ (100 mg twice daily) reduced urinary hydrochlorothiazide (HCTZ) remains the most commonly pre- calcium excretion (4). Lichtwitz suggested this property might scribed antihypertensive medication in the United States (1). In be exploited to prevent calcium-containing kidney stone recur- the treatment of nephrolithiasis, it has been shown that thiazide rence (5), and in 1970 Yendt reported, in uncontrolled studies, and thiazide-like diuretics, especially HCTZ, are commonly not reduced kidney stone recurrence rates using HCTZ in doses used in an evidence-based fashion (3). In this manuscript, we from 100 mg daily to 100 mg twice daily (6). will review the use of thiazide and thiazide-like diuretics in Randomized controlled trials (RCTs) are critical in the eval- randomized controlled trials for the treatment of hypertension uation of stone therapies because of confounding from the and nephrolithiasis. We will place special emphasis on the “stone clinic effect” and regression to the mean. Referral of specific thiazide used, dosage used, and in the case of hyper- patients to a stone clinic is often followed by a reduction in tension whether the thiazide was used in combination with a stone-formation rate (stone clinic effect) independent of drug potassium-sparing diuretic. treatment (7). This likely is the result of changes in dietary habits, especially increased fluid intake. In addition, patients History often seek medical attention for stone disease after a period of The modern era of diuretic therapy began in 1957 when increased disease activity and this may subsequently be fol- Novello and Sprague synthesized the thiazide diuretic chloro- lowed by a period of reduced disease activity regression to the thiazide. Further modification of the benzothiadiazine core led mean (8). to the synthesis of HCTZ and subsequently the thiazide-like At least ten RCTs have examined the effects of several dif- ferent thiazide diuretics on preventing calcium-containing kid- ney stone recurrence (Table 1) (9–18). Seven of the ten RCTs Published online ahead of print. Publication date available at www.cjasn.org. reported a reduction in recurrence rate in treated patients (9– 12,14–16). Two trials that showed no difference in outcome Correspondence: Dr. Robert F. Reilly, VA North Texas Health Care System, Ͻ Medical Service, Mail Code 111, 4500 South Lancaster Road, Dallas, TX 75216. were limited by their short follow-up duration of 2 years Phone: 214-857-1907; Fax: 214-857-1457; E-mail: [email protected] (17,18). A consistent finding in these trials is that stone-forma- Copyright © 2010 by the American Society of Nephrology ISSN: 1555-9041/510–0001 2 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: ●●●–●●●, 2010 medical record documentation that the thiazide was prescribed for calcium-containing kidney stone recurrence were analyzed. Patients on thiazides for Ͻ6 months or who had side effects on uptitration of drug were excluded (n ϭ 8). Of the 107 patients that met these criteria, 102 were treated with HCTZ, 4 with indapamide, and 1 with chlorthalidone. Only 35% of HCTZ- treated patients received Ն50 mg/d; a dose previously shown to reduce stone recurrence in RCTs. Fifty-two percent were prescribed 25 mg daily and 13% 12.5 mg daily; these doses were Figure 1. Chemical structure of thiazide and thiazide-like di- not studied in RCTs. No RCT that we are aware of has used uretics. low-dose HCTZ (12.5 to 25 mg daily) to examine reduction in calcium-containing kidney stone recurrence. Whether this dose would be effective is unknown. tion rate between treated and control groups did not begin to Interestingly, in only 2 of 10 RCTs was hypercalciuria an diverge until after at least 1 year of therapy. Stones too small to inclusion criterion (9,14). Despite this fact, 7 of 8 trials of ade- be detected by imaging studies may be passed in the first few months and obscure beneficial effects of treatment (10). quate duration showed a reduction of kidney stone-formation All but one of the RCTs with thiazide diuretics were con- rate with thiazide diuretics. There are at least two potential ducted between 1981 and 1993 and used HCTZ, bendroflu- explanations for why thiazide diuretics may reduce stone re- methazide, chlorthalidone, trichlormethiazide, or indapamide. currence in those without hypercalciuria. The first is that even Trichlormethiazide is no longer available. Importantly, in the as urinary calcium excretion increases within the “normal” four trials that utilized HCTZ, it was prescribed in high dose range, the risk of stone formation increases. This was shown by (50 to 100 mg daily) (12,16–18). The lowest dose used was 50 Curhan et al. in an analysis of the Nurses Health Studies (NHS) mg daily. The following currently available thiazide diuretics, I and II and the Health Professions Follow-Up Study (HPFS) at the doses indicated, were shown to reduce risk for recurrence (19). An increase in relative risk for kidney stone formation was of calcium-containing kidney stones: indapamide at 2.5 mg/d, seen with urinary calcium excretion Ͼ100 mg/d in NHS I, Ͼ150 chlorthalidone at 25 to 50 mg/d, or HCTZ 25 mg twice daily or mg/d in NHS II, and Ͼ125 mg/d in HPFS. 50 mg/daily. The hypocalciuric action of thiazides is the most likely mech- A recent report showed that thiazide diuretics are often not anism whereby this drug class reduces calcium-containing kid- used in an evidence-based fashion in the treatment of calcium- ney stone recurrence. One small trial involving six healthy containing kidney stone recurrence (3). One hundred and seven subjects without hypercalciuria attempted to establish a dose- patients with a filled prescription for thiazide diuretics that response relationship between HCTZ and urinary calcium ex- underwent a 24-hour urine stone risk factor analysis and had cretion (20). Each subject was maintained for 1 week on increas- Table 1. RCTs of thiazide diuretics in stone prevention Selection/Percent Follow-Up n n Author, Year Treatment Hypercalciuria (years) Treated/ Placebo RR Brocks, 1981 (17) Bendroflumethiazide None 1.6 33/29 NS 2.5 mg TID Scholz, 1982 (18) HCTZ 25 mg BID None 1 25/26 NS Laerum, 1984 (12) HCTZ 25 mg BID None/20% 3 25/25 0.39 Wilson, 1984 (16) HCTZ 100 mg daily None 2.8 23/21 0.48 Robertson, 1985 (15) Bendroflumethazide None 3 to 5 13/9 0.38 2.5 mg TID Mortensen, 1986 (13) Bendroflumethazide None 2 12/10 NS 2.5 mg ϩ KCl Ettinger, 1988 (10) Chlorthalidone 25/ None/13% to 3 19/23/31 25 mg/50 mg/ 0.23 50 mg 15.8% placebo Ohkawa, 1992 (14) Trichlormethiazide Hypercalciuria 2.1 to 2.2 82/93 0.42 4mg Borghi, 1993 (9) Indapamide 2.5 mg Hypercalciuria 3 43/14 0.21 daily Fernandez-Rodriguez, HCTZ 50 mg daily None/52% 3 50/50 0.56 2006 (11) TID, 3 times a day; BID, twice a day; KCl, potassium chloride; RR, relative risk.